Lecture 1

1) Pharmacodynamics does not deal with bioavailability as pharmacodynamics is what drug

does to the body, which suggests that all the drugs has been entered into the body
2) Pharmacodynamics deasl with responses in the body, EC50, efficacy and so on
3) Pharmacokinetics deals with ADMA, Tmax, half life, Cmax, Vd, F and concentration time
relationship.
4) Success rate of phase I, II and III are 70, 33 and 25-30% respectively.

Lecture 2

1) Area under the curve represents how much of the drug is in the plasma over a given time,
expresses the exposure of the drug
2)

3) Bioavailability refers to the drug available to the systemic circulation over time after
administration, not absorption rate constant.
4) Incomplete absorption and pre-systematic/first pass metabolism are the two reasons why F
is usually not one for oral drugs.
5) Polar drugs are usually difficult to have passive absorption into the small intestine.
6) Permeability coefficient in the rate equation is determined by the properties of the drug not
the membrane.
7) Gastric emptying rate is how fast the stomach empty to the small intestine
8) GI motility is how fast the contents are passed to the anus.
9) Vd is the volume of fluid in which a drug would need to be dissolved in order to have the
same concentration in that volume as it does in plasma.
10) Plasma protein binding causes the Vd to be low.
 11) First pass metabolism is when the enzymes at the gut wall breaks the drug down, thus not
absorbed.
12) Phase I and Phase II of drug metabolism. Phase I is the preparatory phase, where the drug is
modified to make it active. Phase II is the synthetic phase, where the drug is conjugated with
other groups to make it more hydrophilic for excretion. Phase I and phase II are catabolic
and anabolic respectively.
13) Metabolic toxicity: often the products of drug metabolism can be toxic especially when the
drug is not conjugated to be removed after action has been carried out.
14) Cytochrome P450 is responsible for biotransformation of most drugs.
15) Polar drugs metabolites are not readily reabsorbed, therefore when they are conjugated,
they are usually removed and not reabsorbed as they became more hydrophilic.
16) Renal excretion rate: amount of drug removed by the kidney per unit time.
17) Renal clearance: volume of blood cleared of drug appearing in urine per unit time
18) Elimination half-life: the time it takes for the plasma concentration to drop by 50%.
19) One compartment model assumes that body is composed of a single homogenous
compartment, which consists of plasma and well perfused tissues.

Pharmacokinetics

1) Efficacy is the measure of the biological effectiveness of the DR complex the drug forms with
the receptor, alpha. The higher the efficacy, the higher the Emax.
2) Chemical antagonism: antagonism at the drug level, where two drugs combining in a
solution and the effect of the active drug is lost
3) Physiological antagonism: antagonism at the tissue/organism level. Two drugs causing
opposing effect that arise through different mechanism, but both will trigger an effect.
Chemical will not trigger any effect
4) Pharmacological antagonism: antagonism at the receptor level. One drug bind to the
receptor and the other preventing it, i.e. competitive and non-competitive inhibition
5) Graded response is a response that varies in the magnitude in a dose-dependent manner.
6) A quantal response is a all-or-none response. It is the number of subject responding to the
drug that varies in a dose-dependent manner.

GPCR

1) Seven transmembrane spanning receptors (heptahelical structure)

2) Gaq is for smooth muscle contraction. Gai ns to inhibit smooth muscle contraction and
inhibit the release of transmitter. Gas is for heart muscle contraction, smooth muscle
relaxation and glycogenolysis.
3) Desensitization (tachyphylaxis, tolerance) includes uncoupling (G protein from effector),
internalization (arrestin internalize the GPCR) and down regulation (proteolytic
degradation/reduced synthesis).
4) GRK (GPCR Kinase) is required for homologous desensitization to phosphorylate the GPCR
receptor.
5) GPCR differs in the N terminus length and location of agonist binding
6) GPCR 3rd cytoplasmic loop interacts with the G protein
7) Phosphorylation at the C-terminal tail (not 3rd loop) of Ser and Thr results in receptor
desensitization
8) Gamma subunit of GPCR is anchored to cell membrane via a process known as prenylation.
9) Cholera toxin acts on Gas, where it keeps activating adenyl cyclase, excessive release of fluid
 10) Receptors Gai inhibits adenyl cyclase and therefore no formation of cAMP.
11) Both DAG and IP3 are 2nd messenger
12) DAG will remain in the membrane as it is hydrophobic than IP3, binding to PKC to form
Arachidonic Acid
13) Desensitization works when the site other than the normal phosphorylating site is
phosphorylated. PKA/ PKC/ GPCR (which is at the C terminal) are phosphorylated at residues
different from the usually targeted by GRKs will be desensitized.
14) Arrestin activate MAP kinase for endocytosis of GPCR.

Nuclear Receptor

1) Binds to DNA response element in the promoter region of target genes as homodimers or
heterodimers
2) Ligands and drugs are highly lipophilic, located in nucleus or cytoplasm
3) The onset of biological responses is slow as transcription is usually slow
4) Class I: steroid receptor family, Hybrid class: Thyroid/Retinoid receptor family and Class II:
Orphan receptor family
5) Usually bound to Hsp90 proteins in the cytoplasm when ligand/drug is not bound
6) There is ligand binding domain, transcription activating domain and DNA binding domain.
7) DNA binding domain usually have zinc fingers
8) Nuclear receptor is involved in carcinogenesis where the gene transcription induced
increases the DNA proliferation and alteration of protein expression, leading to mutation
and carcinogenesis.
9) All homodimers are class I. Other heterodimers require RXR as a partner. RXR is a receptor
that is bound by 9-cis Retinoic Acid, even Hybrid and Class II receptors require RXR as
heterodimer.
10) Nuclear receptor modes of activation: genomic (normal), tethered where Fos and Jun
proteins are required to modulate the function, non-genomic where the dimerized receptors
bind to the cell membrane and regulate kinase and phosphatase activity in the cytoplasm
and ligand independent activation, which means it is constitutively bound even without the
presence of ligand.

Transmembrane Receptor

1) Anchored in membrane with kinase activity in the receptor itself.

2) Receptor Tyrosine Kinase (insulin receptor, Human epidermal growth factor/HER, PGDF,
VEGFR)
3) HER1 is also known as EGFR
4) Receptor Serine/Threonine Kinase (TGF-b, Activin and Inhibin, BMP)
5) Receptor Guanylyl Cyclase (Atrial Natriuretic Peptide/ANP Receptor, GC-A, GC-B and GC-C
receptor)
6) Proteins that bind to RTK has SH2 domains to bind to the phosphorylated Tyrosine on the
receptor.
7) Only RTK has the PLC, PKC, MAP Kinase pathways
8) PKA: activated by cAMP (Gas)
9) PKB: activated by PIP3 (RTK, cytokine JAK pathway), require PDK1 and PH domain to bind to
PIP3, but still need SH2 domain to bind to RTK.
10) PKC: activated by DAG (Gas and RTK)
 11) TGFB is usually for fibrosis, growth arrest, promote apoptosis, cancer, atherosclerosis and
inflammation.
12) Type II (binds to TGF-B first and gets phosphorylated first) and Type I (dimerise with Type II
and bind to TGF-B, the Type II phosphorylate Type I) receptors of RSTK.
13) Proteins that bind to the phosphorylated Type I receptor will require MH2 domain instead of
SH2 (RTK) domain or PH (PIP3) domain.
14) RSTK follows R-smad pathway.
15) MH1 domain is a DNA binding domain.
16) R-smads (smad 2 and smad 3) will be phosphorylated, Co smad (Smad 4) will not be
phosphorylated and will bind to the phosphorylated R smad and I-smad (Smad 6 and Smad
7) will also not be phosphorylated as there is no SXS residue at the end.
17) I smad will bind to R smad and inhibit it. I smad does not have MH1 domain.
18) Smad 2/3 and smad 4 will form a trimer (R-smad, R-smad and Co-smad), where Smad 2/3
are the only ones that are phosphorylated.
19) Guanylyl cyclase is a single-transmembrane receptor, converting GTP to cGMP
20) ANP and BNP binds to GC-A and CNP binds to GC-B. Guanylin and Uroguanylin binds to GC-C
receptors.
21) GC-A and GC-B produces cGMP and activates PKg, PDE and ion channels.
22) NPR-C is the clearance receptor: binding to ANP, BNP and CNP.
23) GC-A, GC-B and GC-C are mainly found in the CVS, skeletal system and GI tract.

Cytokines Receptor

1) Does not have kinase activity in the receptor itself, require other kinase such as JAK to help
phosphorylate the proteins.
2) Monokines by monocytes/macrophages, lymphokines by lymphocytes and interleukin by
leukocytes
3) Target cell interaction via autocrine (the cell target itself), paracrine (a cell targets other
nearby cells without gap junction proteins) or endocrine (a cell targets adjacent cells via gap
junction proteins)
4) Effector responses: pleiotropic (one cytokine has multiple different effects on different types
of target cells), redundancy (one effect can be triggered by many different cytokines),
synergistic (cooperative effect of multiple cytokines) and antagonistic (inhibition of one
cytokine effect by another)
5) Type I is for cytokines that are not from interferon and type II is for interferon
6) Erythropoietin (EPO) and Growth hormones (GH) are from single chain receptor family,
which means that they will dimerise together.
7) Type I has WSxWS motif, which is the only thing that is different from Type II.
8) Type II is the interferon (IFN) receptor family, which also has Type I (IFN a and B) and Type II
(IFN gamma)
9) All types of IFN Receptor family (Type I and Type II) bind to the GAS response element, with
exception of IL-28R that binds to ISRE and IL-22R that activates MAP Kinases.
10) Desensitization of Cytokine receptor requires SOCS, PIAS and SHP proteins that will bind to
phosphorylated JAK at different sites to prevent further phosphorylation of JAK, rendering it
inactive.
11) STAT and other proteins that bind to phosphorylated JAK will have SH2 domain, just like RTK.
MH2 is for RSTK
12) TNFR2 will be entirely pro-inflammatory and anti-apoptotic, whereas TNFR1 has both
apoptotic and anti-apoptotic characteristic due to the presence of TRADD and FADD/death
 domain. Anti-apoptotic TNFR will require NFkB and MAP-K proteins. Apoptotic TNFR1 will
require active caspase-8 to trigger apoptosis.
13) IL-1 does not belong to either Type I or Type II receptor.
14) IL-1RII serve as a decoy receptor
15) IL-1Ra serve as a IL-1 receptor antagonist
16) ST2 receptor can act as a decoy as well as the soluble domain will bind to the Il-33 but not
trigger a response.
17) IL-1 receptors do not trigger JAK pathway.

Ion Channels

1) Phospholipid bilayer act as a parallel capacitor and resistor

2) Membrane potential is generated by the differential distribution of ions.
3) Na+ channel blockade decrasese the rate of rise of the A.P and decrease the amplitude of
the A.P.
4) When an A.P is propagated to the Ca2+ channel of the T-Tubule, the Ca2+ opens and influx
of Ca2+. This influx activates the RyR receptor on the sarcoplasmic reticulum, releasing more
Ca2+ from SR. The Ca2+ will bind to myosin and actin to trigger muscle contraction. SERCA
on the SR will pump the Ca2+ back into the SR.
5) In the smooth muscles, the Ca2+ binds to Calmodulin (CM) and activate MLCK (Myosin light
chain kinase).
6) The blockade of DHP receptor in HEART is used in treatment of angina (inadequate O2
supply) and supraventricular tachyarrhythmias (abnormal fast heartbeat)
7) The blockade of DHP receptor in smooth muscles case dilation of peripheral arterioles and
reduce blood pressure, is used in the treatment of hypertension.
8) GABA will activate GABA-gated chloride channel, causing an influx of Cl-, thereby causing a
hyperpolarization of the membrane potential, harder to trigger an A.P.
9) GABA channel has 2 regulatory sites, benzodiazepine site and barbiturate (phenobarbital)
site.
10) Benzodiazepine potentiate GABA actions by increasing the frequency of GABA-induced
channel opening
11) Phenobarbital increases frequency and duration of opening.
12) Neuromuscular blocking drugs: a) non-depolarising drugs act as antagonist at nicotine
receptors b) depolarising drugs act as antagonist at nicotine receptors, which causes a
persistent depolarization followed by desensitization of the nicotinic receptors. Perhaps Na+
channels are unable to de-inactivate due to closer membrane potential.
13) Cystic fibrosis is caused by the mutation in the epithelial chloride channel CFTR, having a
deletion of phenylalanine at position 508, the defective transmembrane receptor cannot
reach the surface membrane. The loss of CFTR activity leads to dehydration in the airway
epithelia, thickening mucus and this will promote bacterial growth and lung infection.
14) Long QT syndrome is caused by the mutation in the cardiac K+ channels. The loss of function
causes delayed repolarization of the A.P.

Adverse Drug Reaction

1) Therapeutic Index = TD50/ED50

2) High TI means good therapeutic effect as only if high dose is provided will give toxicity to
50% of subjects.
3) ADR is an unwanted/unintended and undesirable/noxious effect of a drug at the normal
dose. This requires discontinuing the drug, modifying the dose, necessitating hospital
admission and resulting in temporary or permanent harm, disability or death
4) ADR occurs frequently, cause morbidity and mortality, account for at least 5% of all hospital
admissions, up to 40% life threatening in kids, incur high medical costs
5) ADE is an untoward medical occurrence of a drug which does not necessarily have a causal
relationship with treatment. ADE can be associated with inappropriate use of drug or
medication errors or even drug-drug interactions when more than 1 drug is consumed at a
time.
6) Type A (augmented): common 80%, dose-dependent, predictable, low mortality, non-
immunologic
7) Type B (bizarre): 10%, dose independent, unpredictable, high mortality, unrelated to
pharmacological action, hypersensitivity (too strong immune system), idiosyncratic (does not
occur in other patients using the same drug). This is immunologic.
8)

9) Larger molecules are more likely immunogenic, or small molecule drugs forming simple
chemical-carrier complexes (hapten) can be immunogenic
10) Routes of administration that have higher chance of hypersensitivity, with highest to lowest,
topical, IntraMascular injection /Intravenous injection, oral
11) Idiosyncratic does not trigger allergen IgE interaction. Occur when the mast cells (activated
in allergy and anaphylaxis) are activated.
 12) Examples of idiosyncratic reactions include general anesthetic gas halothane which could
cause hyperthermia, and anti-malarial drug primaquine that can cause hemolytic anemia in
G6PD patients.
13) Type C (chronic): related to both time and dose, cumulative dose and long-term use
14) Type D (delayed): time-related, dose related, apparent sometime after use of drug
15) Type E (end of dose): withdrawal syndrome

Practical

1) For plasma drug concentration against time curve, for different F value, the time at which
the peak plasma concentration is reached remains the same, the time is not affected by
changes in bioavailability. The rate of decrease of plasma drug concentration remains the
same as well. This is because it is dependent on Kel instead.
2) High Vd means low Kel because the drug is harder to get removed as they are in the tissues.